Approaching enzymatic catalysis with zeolites or how to select one reaction mechanism competing with others

Approaching the level of molecular recognition of enzymes with solid catalysts is a challenging goal, achieved in this work for the competing transalkylation and disproportionation of diethylbenzene catalyzed by acid zeolites. The key diaryl intermediates for the two competing reactions only differ in the number of ethyl substituents in the aromatic rings, and therefore finding a selective zeolite able to recognize this subtle difference requires an accurate balance of the stabilization of reaction intermediates and transition states inside the zeolite microporous voids. In this work we present a computational methodology that, by combining a fast high-throughput screeening of all zeolite structures able to stabilize the key intermediates with a more computationally demanding mechanistic study only on the most promising candidates, guides the selection of the zeolite structures to be synthesized. The methodology presented is validated experimentally and allows to go beyond the conventional criteria of zeolite shape-selectivity.

1. The schemes of the mechanism for the DEB disproportionation should be provided in the manuscript.
Response: Following the Reviewer's recommendation we have included the mechanism for DEB disproportionation in the revised manuscript. For clarity, the original Scheme 2 has been split into two Schemes. The new Scheme 2 includes the alkyl-transfer pathway for the three possible competing processes: transalkylation, disproportionation and dealkylation. The new Scheme 3 includes the diaryl-mediated pathway for the competing transalkylation and disproportionation, together with the OSDA mimic and the key diaryl intermediates.
Scheme 2. Alkyl-transfer pathway for transalkylation of diethylbenzene with benzene and competitive dealkylation yielding ethene and disproportionation producing triethylbenzene.
Scheme 3. (a) Diaryl-mediated pathway for the transalkylation of diethylbenzene with benzene and for the competing disproportionation yielding triethylbenzene represented by the red bonds in all structures. (b) Structures of the OSDA mimic and of the diaryl intermediates for transalkylation (Itrans) and disproportionation (Idisp).
2. The proton shift steps are computed on the pure silica zeolites with periodic models. However, the interactions among the net positive charges (on the intermediates in the pure silica zeolite) in periodic models may cause the error in the energy calculations. Thus, the authors should confirm that the net positive charges in the periodic models do not affect the energy calculations.
Response: The Reviewer raises here an important point regarding the reliability of periodic calculations for charged systems, since it is true that the interactions among the net charges in periodically repeated cells might lead to wrong energies. To confirm this is not the case we have used more realistic Al-containing neutral models in which the positive charge on the organic species is compensating the negative charge generated by the substitution of one framework Si atom with an Al atom. Then, we have calculated the energy profiles for the four diaryl-mediated pathways considered in this study and we have compared the energy profiles obtained with the charged (pure Si framework) and with the neutral (Al-containing framework) models.
The results for IWV and MOR structures were taken from a previous study in our group, published in J. Am. Chem. Soc. 2021, 143, 10718−10726, and we have now expanded this study to UTL containing larger 14-ring channels and to BOG containing narrower 10-ring channels, to be sure that the results reported are correct irrespectively of the size of the channels. Al positions for each zeolite were chosen by intrinsic stability criteria placing one unique Al per unit cell. The most stable locations for Al are T1 in BOG, T3 closely followed by T6 in IWV, T4 in MOR and T11 in UTL, as summarized in new Table S5 in the revised Supplementary Information. Since the T11 site in UTL is at the intersection between the 12-ring and the 14-ring channels, the two possible locations considered in the original manuscript for the mechanistic study, UTL(cha) and UTL(int) were also included in the Al-containing models.   3. The energy barriers of the proton shift steps are compared in part 2.2. However, compared with the proton shift steps, the alkyl-transfer step of the two routes (transalkylation and the disproportionation) may be more sensitive to the zeolite confinement, thus the reaction barriers and transition states of the alkyl-transfer step for the DEB transalkylation and disproportionation routes should be computed and compared in the manuscript.
Response: In a previous work (JACS 2021, 143, 10718) we studied extensively the two possible pathways (alkyl-transfer and diaryl-mediated) in two zeolite structures, MOR and IWV. We found that the carbonium ion intermediates involved in the alkyl-transfer pathway are quite unstable, and that the transfer of a proton or an ethyl group between the organic fragment and the zeolite framework imply higher activation energies than the proton shifts in the diaryl-mediated pathway. However, as pointed by the Reviewer, these energies might be more sensitive to the zeolite confinement and following his/her recommendation we have now calculated this pathway also in BOG and UTL zeolites, which produce experimentally the highest (4,8%) and lowest (0%) amount of ethene, respectively. These results are summarized in new Supplementary  Table R1 below. However, since the alkyl-transfer pathway is not competitive for the transalkylation reaction and the disproportionation reaction is in all cases more energetically demanding, these data have not been included in the revised manuscript to avoid making it unnecessarily long. Reviewer #2: The authors describe a new method for designing zeolite catalysts as enzyme-like catalysts on transalkylation and disproportionation of diethylbenzene competing on zeolite catalysts. First, the authors narrowed down the zeolite structures based on the binding energy (BE) of OSDA having a structure similar to that of the reaction intermediate. The zeolite structures were further narrowed down based on the knowledge of activity-structure (pore size and channel system) relationship for the transalkylation reaction of diethylbenzene over zeolite catalysts. For the candidate zeolite structures, the BE of the intermediates of the two competing reactions, i.e., BE of I_trans and BE of I_disp, were evaluated as the descriptors of the activity and selectivity of the reaction. In addition, the activation energies (Ea) of the transalkylation and the disproportionation reactions were also evaluated as other descriptors. Based on the descriptors and the experimental reaction results, the authors concluded that the ratio of BE of intermediates relates to the selectivity, and the transition state energies of the intermediates relates to the reaction rate. These results indicate that structural control of zeolite can control the BE and the transition state energies of the intermediates and thus achieve enzyme-like selective reactions. The results of this study will be of interest for the development of zeolite catalysts of great practical importance. However, there appear to be logical or scientific flaws. I would suggest that the authors address the following comments: 1. On page 8, "Despite the differences in methodology and model, a good match between the FF and DFT energetics is observed…": What is the criterion for judging whether the match is good or not? The FF calculation results of BEA, IWV, and MOR do not show less than 1 of I_disp/I_trans. 2. In Fig. 7(a), IWR is out of the trend. The authors explained that this is due to the overstabilization of I_disp at the intersection between 12R and the two 10R channels causing slow diffusion of TBE. What is the overstabilization? How is it different from the simple stabilization described by the BE of I_disp? Please explain more about the overstabilization.

Response
Response: We thank the Reviewer for noticing this inadequate use of the word overstabilization, which has been corrected in the revised manuscript. The reason for IWR being out of the trend in Fig 7(a) is that the Idisp intermediate is very stable at the intersection between the 12-ring and 10-ring channels, and such high stability makes the diffusion of TEB slow. The sentence in page 19 of the revised manuscript has been modified as follows: "In contrast, less TEB than expected from the theoretical BE ratios 3. In Fig. 7(b), there seems to be a trend that r_trans increases with BE I_trans. But, the authors concluded that there is no correlation between them. The authors should give a convincing explanation for this conclusion.
Response: As indicated by the Reviewer, there seems to be a trend that rtrans increases with BE Itrans, but the trend is not fully consistent along the dataset and the quantitative correlation is not good. For instance, two of the three zeolites with the largest BE Itrans, MOR and BOG, exhibit the lowest reaction rates, ⁓ 300 molEB/molacid h, while the most active catalyst, IWV, is the one with the lowest BE, which is opposite to expected. There are three zeolites with similar reaction rates of ⁓ 600-700 molEB/molacid h with BE Itrans ranging from -145 (the strongest BE) to -110 kJ/mol (quite weak) highlighted in yellow Figure R1. And there are three zeolites with nearly the same BE Itrans, between -102 and -105 kJ/mol, with reaction rates ranging from 1000 to 2000 molEB/molacid h, highlighted in pink in Figure R1. Altogether, there is not a clear relationship between BE and reaction rate. Taking to account the Reviewer's comment, the sentence in page 21 has been modified as follows:"On the other hand, there seems to be a rough trend in the plot of the experimental reaction rates for transalkylation rtrans and the calculated BE for Itrans, with higher reaction rates in the zeolite structures that stabilize less the Itrans intermediates (Figure 7b), but the trend is not consistent along the dataset and the correlation is not good." Figure R1. Correlation between experimental reaction rates for transalkylation rtrans and DFT calculated BE of the diaryl Itrans intermediate. Fig. 8, only six zeolites are evaluated, while eight zeolites are evaluated in Fig. 7. Why did the authors exclude FAU and ITT in Fig. 8? A er adding the data of FAU and ITT in Fig. 8, the correlation between Ea_exp and Ea3_DFT should be compared to that between r_trans and BE I_trans to support their conclusion that Ea should be calculated to predict the catalytic activity (reaction rate).

In
Response: In Figure 7  In any case, as explained in the previous point raised by the Reviewer, the rough trend in the plot of reaction rate rtrans and BE Itrans is opposite to expected, with the most active zeolites being those that stabilize less the diaryl Itrans intermediate. In contrast, the correlation between experimental and calculated activation energies shown in Figure 8 is direct, and the experimentally determined reaction rates rtrans increase as the calculated activation energies decrease, following the expected relationship according to kinetics.
Minor comments: 1. On page 14, "…the planarity or the two aromatic…" might be "…the planarity of the two aromatic…".
Response: Thanks for noticing, it was a typo and it has been corrected in the revised manuscript.
2. It might be better to explain dotted lines in Figure 1.
Response: As suggested by the Reviewer we have indicated in the caption of Figure 1 the meaning of the dotted lines: 3. Table 1: What is "kJ/mol I"?
Response: As indicated in page 9 of the revised manuscript, to calculate the binding energies using DFT "the zeolite pores were filled with the maximum number of molecules possible, given in column n in Table 1." The BE Itrans and BE Idisp given in Table 1 are "binding energies per mole of diaryl intermediate" and this is why they were given as kJ/mol I. However, we agree with the Reviewer that the units are kJ/mol and it has been corrected in the revised manuscript.